The invention relates generally to the treatment of various disorders caused by or associated with relatively elevated levels of certain high molecular weight blood plasma components, particularly those rheologically active macromolecules that generally are larger than about 500,000 Daltons (500 kDa) in weight or greater than about 200 xc3x85 in diameter. Elevated levels of such plasma constituents are found in chronic, age-related, degenerative, and/or inflammatory diseases associated with the accumulation of and/or deposition of biological substances that result in or are associated with disturbances of blood rheology, extra-cellular matrix composition, and intrinsic endothelial cell function. The invention relates specifically to Rheopheresis(copyright) blood filtration treatments, and associated membrane differential filtration devices, methods, treatment apparatus and systems for such diseases, and more particularly to the treatment of atherosclerotic and/or thrombotic diseases such as coronary, renal, peripheral and cerebrovascular diseases as well as perfusion deficit diseases such as Age-related Macular Degeneration (AMD), Diabetes, Rheumatoid Arthritis and Alzheimer""s Disease. Such methods include but are not limited to VasoTherapy(trademark) and AngioTherapy(trademark) using the RheoFilter AR 3000 and RheoFilter AR 4000 hollow fiber membranes respectively. Thus, for the purposes of this application, as will be evident from the context, the term xe2x80x9crheopheresisxe2x80x9d applies broadly to each of methods and filters collectively, although they include different products, are directed toward different disease manifestations and are studied, labeled, tested, approved, utilized and reimbursed differently.
Circulating blood components that are suspended in or dissolved in the plasma can be loosely classified into (1) small (low molecular weight compounds), (2) medium or xe2x80x9cmiddle moleculesxe2x80x9d and (3) large (high molecular weight compounds). The relationship between the size and weight of these compounds is determined by: (1) their density, which is directly related to the three-dimensional conformational structure (protein folding) of the isoform expressed and (2) their biologically active form (monomer vs. multimer). Small plasma compounds are typically less than 75 xc3x85 in their shortest axis diameter and have low molecular weights generally less than about 120,000 Daltons (120 kDa). Middle molecules occupy the range roughly from about 75 xc3x85 to 150 xc3x85 in their shortest axis diameter, weighing 120 kDa to 500 kDa. Large plasma components are those typically larger than about 150 xc3x85 in their shortest axis diameter weighing generally greater than 500 kDa.
Typical low molecular weight moieties include substances such as albumin (69 kDa) and certain cytokines such as tumor necrosis factor (TNF- alpha) and certain growth factors (VEGF, TGF- beta, etc.). Middle molecules may include the gamma immune globulins (xcx9c125 kDa) and similar-sized particles. The high molecular weight group includes the xe2x80x9crheologically active macromoleculesxe2x80x9d (RAM) compounds such as the alpha-2 macroglobulin tetramer (xcx9c900 kDa), lipoproteins A and B, cholesterol isoforms (VLDL, LDL, IDL, etc) and other beta lipoproteins(xcx9c850 kDa), fibrinogen, IgM, and many others. Many of these compounds can exist in numerous related isoforms, such as racemers, enantiomers, oxidized and reduced forms, and so on. Frequently, the biologically active state of plasma component particles is conferred in multimeric conformations such as IgA pentamers, TNF- alpha dimers, vitronectin 16-mers and von Willebrand trimers. Often their biological activity will change depending upon the isoform expressed. They are often categorized into groups, classes, families, and superfamilies.
Many high molecular weight RAM compounds are associated with various diseases that may be treated according to the methods of the present invention.
Historically, diseases have been classified as being either xe2x80x98acutexe2x80x99 or xe2x80x98chronicxe2x80x99 in nature. Recently it has been determined that many chronic illnesses, especially some age-related, degenerative, and inflammatory diseases, result from pathologies involving either: (1) a slowly progressive, chronic, time-dependent accumulation of biological moieties into tissues comprised, in some cases, of metabolic debris, or (2) in other cases of the rapid, acute, up-regulated overproduction of these same substances where they can exhibit acute phase reactant behavior.
Irrespective of their origin, mechanism of formation or temporal generation, in those disease states referenced above, these biological products have a tendency to collect within peri-endothelial, capillary, interstitial, and extracellular matrix tissues. Although they are typically distributed across all three body compartments (intravascular, interstitial and intracellular), depending upon their equilibrium constants and the homeostatic disruption, they will often manifest as increased plasma or serum concentrations within the blood circulation itself. Often, these biological compounds are further modified by acetylation, glycation, oxidative or other processes to form less stable isoforms that condense into complex aggregates (atherosclerotic plaques, drusen, neurofibrillary tangles, lipofuscin, amyloid, etc.). Although these aggregates are comprised primarily of proteinaceous moieties, they also contain lipids, lipoproteins, fatty acids, carbohydrates, metals and other non-protein compounds. Thus, the terms xe2x80x9cprotein accumulation-deposition diseasesxe2x80x9d or xe2x80x9cdysproteinemiasxe2x80x9d as has been historically applied to these conditions, is technically a misnomer. Therefore, for the purposes of this application, the term xe2x80x9cRAM accumulation-deposition diseasesxe2x80x9d will be substituted for clarification where appropriate.
Saturated catabolic mechanisms predispose RAM to progressive concentration increases within the blood that primarily and secondarily induce numerous functional disturbances of the endothelium, blood rheology, extra-cellular matrix, microcirculation and/or microperfusion. Elevated serum levels of RAMs have been documented to: (1) cause increases in whole blood and plasma viscosities thus reducing blood flow; (2) promote cell-cell adhesion causing thrombosis, cell clumping and diapedesis; (3) disrupt numerous intrinsic endothelial cell functions, and (4) cause numerous other pathologies which can promote various disturbances in the microcirculation. Such actions are measurable as decreases in capillary perfusion, endothelial cell rupture, atherogenesis, thrombosis, angiogenesis, and other pathological states leading to ultimate end-organ dysfunction or outright failure. Occasionally, primary rheologic pathologies can be so significant that the disturbances can be observed even within the systemic circulation forming procoagulant states and in the extreme - hyperviscosity syndromes, diffuse intravascular coagulation, etc.
Some examples of medical conditions that may be classified as RAM accumulation-deposition diseases are:
Atherosclerotic disease which develops as a result of progressive endothelial cell dysfunction in the presence of progressive deposition of lipid-laden plaques that form preferentially within the intimal walls of coronary, renal, carotid, aortic and certain other arteries throughout the body, often in the presence of hyperlipidemia.
Rheumatoid arthritis which results from the destructive inflammatory reactions occurring in a synovial pannus associated with elevated serum levels of Rheumatoid Factor, various inflammatory proteins, immunologic globulins, integrins, and other compounds, including the chemotactic attraction of activated inflammatory cells, that contribute to the dysfunctional synovial lining of the various joints involved;
Diabetes mellitus which is classically described as an autoimmune disease demonstrating profound pathological effects on the microcirculation and peripheral nervous system, with classically observed disruptions of blood rheology associated with aldose deposition, and other disruptions including: advanced glycation, carbohydrate dysmetabolism, insulin resistance and other pathophysiologic disturbances measured in both the serum and tissues;
Alzheimer""s disease which is associated with the formation of xe2x80x9cneurofibrillary tanglesxe2x80x9d or accumulations of complex deposits comprised primarily of Tau proteins and beta-amyloid proteins in specific brain tissues, and is also associated with decreased local blood flow to those same brain tissues;
Age-related macular degeneration (xe2x80x9cAMDxe2x80x9d), which is often characterized by the deposition of vitronectin, lipofuscin aggregates called drusen and basilar laminar deposits which form within specific retinal tissues (the retinal pigment epithelium/Bruch""s Membrane complex) and is associated with a disruption of the choriocapillary microcirculation, as well as observed increases in the serum levels of certain circulating RAMs (cholesterol, fibrinogen, etc.).
Procoagulant State which is often characterized by (relatively increased serum concentrations of certain thrombogenic macromolecules causing) a tendency to relatively more readily activate the coagulation cascade in a patient.
RAMs are typically large, high molecular weight biological moieties, comprised primarily of proteins and lipids, and secondarily of fatty acids, carbohydrates and other compounds that are found in the general blood circulation, in the membranes of blood cells, expressed on cell surfaces (especially endothelial cells), deposited in the extra-cellular matrix and within the interior of cells of certain tissues. RAMs are associated with unique pathological roles and physiological effects as described above.
In addition to their unique biochemical roles, RAMs exert numerous secondary and tertiary effects on the blood and blood rheology processes, including acting as buffers, osmotic agents, oncotic agents, signaling molecules, and so on. More specifically, many RAMs exert complex, simultaneous and integrated rheological effects on the blood cells themselves including: (1) red cell aggregation and viscoelasticity; (2) leukocyte adhesion, morphogenesis and diapedesis; and (3) platelet rouleaux formation. These actions are primarily mediated by the regulatory effects of RAM on gene activation and surface receptor expression on these blood cells, and ultimately reflect on both whole blood and plasma viscosities, with primary control over blood flow, shear stress and perfusion within the microcirculation. These effects are transmitted to the macrocirculation via the vaso-vasorum that nourishes the entire vascular system. Recent research also points to certain RAMs acting as triggers for various gene expressions, and mRNA transcription activity as well, especially in their role in apoptosis (programmed cell death).
Examples of circulating soluble or suspended RAMs commonly measured in the serum of patients are: alpha-2 macroglobulin, fibrinogen, triglycerides, beta-lipoproteins like LDL cholesterols (especially the oxidized forms), fibronectin, vitronectin, IgM, and other immunoglobulins, von Willebrand factor, lipoprotein A, to name just a few. Of course, there are some RAMs less than 500 kDa, however most RAMs are greater than 500 kDa. One object of the present invention is the safe, rapid, efficient and simultaneous depletion of at least two or more of these RAMS from the systemic circulation and by their extraction from the tissues. The close association of these markers and the diseases that they herald and/or play a causative role, allow these moieties to be commonly referred to as xe2x80x9crisk factorsxe2x80x9d or xe2x80x9cserological markersxe2x80x9d for the development of the diseases with which their serum elevations are correlated (heart disease, stroke, renal failure, blindness, etc., in association with cholesterol, fibrinogen, etc.)
It is now widely accepted that RAM either directly or indirectly participate in the control of virtually every aspect of vascular cellular metabolic activity. They govern the intricate balance of action and reaction that controls the many complex biochemical reactions necessary to maintain health (homeostasis). The precise homeostatic control mechanisms vary from one endothelial population to another, but generally speaking, most RAM can be classified into having one of two actions, promotersxe2x80x94which activate or xe2x80x9cup-regulatexe2x80x9d a particular biological action, pathway or processxe2x80x94and inhibitorsxe2x80x94which suppress or xe2x80x9cdown-regulatexe2x80x9d a particular biological action, pathway or process. Interestingly, depending upon their local concentration levels, many RAM can exhibit both actionsxe2x80x94acting like biological switches.
In health, the body responds to the overproduction or under-catabolism of a particular substance by increasing its endogenous production of mediators, which can include a cascade of promoters, inhibitors, or both, as the case may be designed to reduce its concentration back down to normal limits. Conversely, any underproduction or over-catabolism is counteracted with a concomitant release of mediators that likewise can include a cascade of promoters, inhibitors, or both, as the case may be designed to increase its concentration back up to normal limits. Any prolonged disruption of this delicate balance of promoters and inhibitors can lead to a pathologic deterioration of the clinical state into conditions that ultimately manifest themselves as disease. Many diseases manifest themselves as deficiencies of essential macromolecules, RAM accumulation-deposition diseases are easily differentiated by characteristically being associated with excessive concentrations of macromolecules. It is now thought that these imbalances are initially manifested at the molecular level where chemical reactions located in sub-cellular organelles, usually under protein (enzymatic/hormonal) control, determine the ultimate overt clinical status. However, within the bloodstream itself, numerous homeostatic mechanisms have evolved that are regulated not only by the chemical reactions of certain moieties, such as RAMs, but also are directly affected by the absolute plasma concentrations of these components in circulation, such as the rheologic effects. Often, these effects can be greatly accelerated and exaggerated as can be seen in organ failure like the nephrotic syndrome where intravascular plasma losses induce artificially elevated plasma concentrations of RAMs.
A. Plasmapheresis
Increasingly sophisticated apheresis technologies have contributed to advanced methods of providing the two basic forms of apheresis treatment, namely plasmapheresis and cytapheresis. Plasmapheresis involves the extracorporeal manipulation, depletion and/or removal of certain soluble or suspended elements in the plasma portion of the blood, and then returning the blood so treated to the patient to induce a desired clinical effect. Historically, these methods have been primarily concentrated on modulation of immune pathologies. Plasmapheresis is variously performed in vivo using therapeutic plasma exchange (TPE), immunoadsorption (IA), precipitation (HELP), membrane differential filtration (MDF), and other means.
By way of example, one type of plasma filtration column is described in U.S. Pat. No. 4,619,639 (which issued to Asahi Medical Company, Ltd. in 1986).
B. Cytapheresis
Cytapheresis can be distinguished from plasmapheresis in that it involves the extracorporeal manipulation or depletion and/or removal of various circulating or marrow-bound cellular elements in the blood (red cells, white cells, stem cells or platelets) or specific subpopulations of these cells in order to induce a desired clinical effect. Historically, these effects have been primarily concentrated on modulation of hypercellular pathologies like leukemias, myelomas etc. It is variously performed with centrifuge, membrane differential filtration, and other means.
C. Apheresis Equipment
Several new apheresis methods including membrane differential filtration (MDF) systems, utilizing for instance the PlasmaFlo(copyright) OP-05(W)L and the RheoFilter(copyright) AR2000 blood filters, both manufactured by Asahi Medical Company, Ltd. of Japan, and other such devices, have recently been introduced. These filter combinations have demonstrated the ability to safely and effectively reduce significant concentrations of a broad bandwidth of numerous circulating plasma macromolecules, including; alpha-2 macroglobulin, triglycerides, the cholesterol family of beta-lipoproteins, various immunoglobulins, fibrinogen, advanced glycation modified end products (i.e., AGE-modified lipoproteins), and the like. These MDF apheresis devices employ sophisticated membranes that utilize the presence of porous hollow fibers that sieve out various blood constituents depending upon the pore size in the fiber""s sidewall. Accurate control of the average pore size of the fibers within the filters enables one to selectively sieve out only the particular size or weight macromolecules desired above a certain xe2x80x9ccut-offxe2x80x9d threshold. The RheoFilter AR 2000 for example, has average pore sizes of 250 xc3x85 in diameter (about the size of the typical LDL molecule). In theory, depending upon the pore size cut-offs, several filters of differing pore sizes can be placed in series to remove specific components from the blood of virtually any size range.
Other benefits of MDF systems include the application of plasma separation as that performed by the Plasmaflo OP-05 (W)L that operates using low operating trans-membrane pressures such that virtually no hemolysis of the blood occurs during treatment. This represents a significant advance over the centrifuge technologies currently in wide use in the United States and elsewhere. As would be expected, wherever hollow fiber membranes have been introduced, the use of centrifuge systems has been significantly reduced.
A variety of apheresis treatments have been described over the past thirty years for use with patients having acute illnesses. However, patients with chronic, age-related, degenerative, or inflammatory diseases, especially those manifesting disturbances of blood rheology, differ significantly from the historical acutely ill populations that heretofore have obtained plasmapheresis treatment. For example, chronically ill patients are typically significantly older than patients with acute conditions, often have significant co-morbidities (heart disease, etc.), consume numerous medications, and in general are typically less robust (resilient) than the younger acute patient group. Among other things, since many of the chronic, age-related, degenerative, inflammatory diseases are initiated, moderated, or otherwise associated with a disruption of capillary blood flow and/or a dysregulation of microperfusion to a diseased or failing organ and such a condition is typically systemic, other organ systems may be diminished in their intrinsic functional capacities as well. Accordingly, the use of apheresis to treat such chronically ill patients has been relatively limited. One recent exception is hyperlipidemia.
A. Hypercholesterolemia
Several apheresis systems have recently has been introduced for the treatment for patients with clinically evident, refractory, drug resistant, Type II Familial Hypercholesterolemia - a rare chronic, slowly progressive, ultimately fatal illness. (Matsuda et al., (1995) Artificial Organs 19, 129-134). One observed consequence of the LDL reduction via apheresis both with and without adjunctive lipid-lowering pharmaceutical therapy has been the reduction of the incidence of restenosis after revascularization as well as a reduction of coronary events.
B. Autoimmune Disorders
Apheresis means have been employed to treat various autoimmune disorders. Depending upon the disease itself, its clinical manifestations, and the underlying mechanism of action, apheresis systems have been effective either as primary or adjunctive therapies. Some examples are listed below:
1) Lupus Erythematosis
Standard treatment of Lupus Erythematosis consists of corticosteroids and immunosuppressive drugs. Plasmapheresis has been shown to impart additional benefit to patients suffering from Lupus Erythematosis when used alone to treat acute symptoms or prior to immunosuppressive therapy (Euler et al., (1996) Transfius. Sci. 17, 245-265). The apheresis methods are employed to remove circulating antibodies, immune complexes and antigens that contribute to the etiology and/or progression of the disease.
2) Rheumatoid Arthritis
Apheresis has also been used to treat rheumatoid arthritis, a chronic and debilitating autoimmune disease which leads to inflammation and deformity of the joints (U.S. Pat. No. 5,782,792). The standard treatment involves weekly outpatient apheresis sessions utilizing a column containing Protein A immobilized on an inert silica matrix for 10 to 12 treatments. The Protein A binds to and removes antibodies, immune complexes and antigens that contribute to the symptoms of rheumatoid arthritis. A similar method has also been described for treatment of thrombotic thrombocytopenia purpura (U.S. Pat. No. 5,733,254).
C. Cryoglobulinemia
Patients diagnosed with cryoglobulinemia have been treated using various apheresis methods with successful results (Russo et al., (1996) Transfus. Sci. 17, 499-503; Siami et al., (1995) ASAIO J. 41, m315-m318). The final results of these studies indicated that treatment with apheresis resulted in a reduction in plasma viscosity and subsequent improvement in rheology and in the function of affected organs.
D. Age-related Macular Degeneration
Age-related macular degeneration (AMD) is a chronic, progressive, degenerative eye disease of unknown etiology. AMD is characterized by progressive loss of central vision, and is the most common cause of legal blindness in patients over age 65 in the industrialized world. Over fifteen million Americans are currently estimated to be diagnosed with signs and symptoms of AMD, most commonly in persons aged 65 and older, with over one and a half million rendered legally blind and nearly two million new cases being diagnosed annually. AMD is divided into xe2x80x9cDryxe2x80x9d and xe2x80x9cWetxe2x80x9d forms depending upon the morphological characteristics associated with the observed eye pathology.
Recently, Allikmets and others presented landmark research that implicates a defective gene in the pathogenesis of AMD (Allikmets et al., (1997) Science 277, 1805-1807). The gene, which is located at the 1p21 locus, codes for the manufacture of the ATP Binding Cassette transporter retina-specific (ABCR) protein. This superfamily of proteins is believed to be responsible for energy-dependent transport of various substances across retinal membranes, thus promoting the clearance of the retina""s waste by-products of vision. In both rod and cone outer segments, hundreds of pigment disks are shed into the retinal pigment epithelial layer (RPE) of the retina daily. There the RPE cells phagocytize the pigment disk material, preparing it for transport across Bruch""s membrane to be removed by the adjacent choriocapillary blood supply.
The reported genetic defect in AMD renders this waste removal pipeline less effective, allowing accumulations of debris to collect in the posterior retina at the layer of the RPE/Bruch""s complex. When clinically evident, this debris is believed to collect in deposits termed drusen or basilar laminar deposits, depending upon the location of the deposit. It is believed that these deposits are directly toxic to surrounding retinal tissues, and that they may play a role in the progression of AMD. If so, depletion and/or removal of these deposits is hypothesized to have a beneficial effect on a patient""s vision. Current research attempts to improve patients"" vision by laser applications to these drusen deposits have been disappointing.
Other recent research supports the notion that AMD is concurrently associated with a dysfunction of the microcirculation in the posterior retina (Freidman et al., (1997) Am. J. Ophthalmol. 124, 677-682; and Grunwald et al., (1986) Ophthalmology 93, 590-595).
This body of research has repeatedly documented decreases in retinal blood flow, impaired choriocapillary perfusion, increased vascular resistance, and pulsatility, along with decreased blood volume and various morpho-pathologic changes in the retinal capillary vessels themselves. Although the precise etiology and mechanism of action for the occurrence of these changes are not yet understood, it is believed that AMD is promoted through a complex interaction of multiple etiologies. Therefore, until now, other than laser photocoagulation, there has been no therapy widely recognized to be effective and therefore commonly recommended for the treatment of this disease, and most certainly in its early xe2x80x9cdryxe2x80x9d stages.
Brunner, Berrouschot and others have documented that subsequent to MDF apheresis, reduction of rheologic factors induces numerous clinically evident rheological changes, including reduction of both whole blood and plasma viscosities, reduction of red blood cell aggregation, promotion of capillary blood flow, and enhancement of intrinsic endothelial cell function (Brunner et al., (1995) Intl. J. Artif. Organs 18, 794-798; Brunner et al., (1991) JAMA 18, 63-65; Brunner et al., (1996) Transfus. Sci. 17, 493-498; Widder et al., Invest. Ophthalmol. Vis. Sci. 38, s1-1176;
Berrouschot et al., (1998) Acta. Neurol. Scand. 97, 126-130). These prior studies, however, failed to optimize timing intervals associated with apheresis treatments and therefore were unable to demonstrate maximal improvement in clinical outcomes. Specifically, the AMD study utilized a monthly interval between individual apheresis treatment cycles of two session which was insufficient to maintain reduced levels of RAMs. The ischemic stroke study utilized a protocol in which apheresis treatment was not given until six or more hours following stroke. The apheresis treatment protocol was also considered to be unsatisfactory because of the extended period of time prior to treatment (six hours).
E. Cancer
Other researchers have discovered and used a selective form of apheresis designated UltraPheresis(trademark) as an innovative approach for the treatment of cancer (U.S. Pat. No. 4,708,713 issued to Rigdon Lentz). UltraPheresis(trademark) removes a low molecular weight fraction of the blood containing immunosuppressive components, known as tumor necrosis factor (TNF-alpha) soluble receptors, from the blood of the cancer patient. When TNF-alpha receptors are removed, a patient""s natural killer cell activity increases and is better able to recognize and attack the malignant tissue. UltraPheresis(trademark) therapy thus is intended to stimulate the natural immune response that is suppressed by malignant tissue expression of tumor recognition suppressive agents. UltraPheresis(trademark) can be distinguished from Rheopheresis(copyright) blood filtration because the former seeks to target the depletion of a specific small molecular weight fraction (less than 100 kDa) from the patient whereas the latter depletes the entire bandwidth of the high molecular weight fraction (greater than 500 kDa).
F. Renal Diseases
Apheresis has been shown to be an effective method for the treatment of many types of renal diseases including glomerulonephritis, glomerulosclerosis, nephrotic syndrome and many others as well. (Harada et al., (1 998) Ther. Apher. 2:193-198). However, the present invention is the first to contemplate the simultaneous use with dialysis for the secondary prevention and prophylaxis of the vascular complications associated with hemodialysis treatment.
G. Acute Coronary Syndromes. Brain Stroke and other Vascular Diseases
The utility of various apheresis methods in the treatment of various vascular diseases is currently under investigation. While the precise mechanisms of atheroma development have not been entirely defined, the most recent consensus states that atherosclerotic lesions develop as the result of biochemical cascades initiated in the presence of increasing plasma concentrations of certain lipids, proteins and other macromolecules that promote accumulations of proteaceous lipid-laden plaques within certain arterial walls. If these plaques rupture and lead to thrombosis and occlusion in the heart, this is called a heart attack, in the brain, this is called a stroke, in the limb this blood clot may lead to gangrene and amputation. Aneurysmal ruptures may follow a similar progression.
Apheresis methods, and membrane differential filters, like the RheoFilter(trademark) MDF system in particular, have demonstrated their ability to remove circulating plasma macromolecules that have been implicated in capillary (endothelial) dysfunction, atherogenesis and thrombosis. The mechanisms are complex but likely include alterations of rheologic factors promoting synergies of: decreasing plasma viscosity, decreasing whole blood viscosity, decreasing erythrocyte aggregation, increasing shear stress and enhancing intrinsic endothelial cell function. Membrane differential filtration achieves these objectives, primarily through reductions of circulating macromolecules, especially the RAMs within minutes to hours.
For apheresis applications involving the treatment of vascular diseases, the ability to remove RAMs is of utmost importance. Recent research has demonstrated that fibrinogen, LDL, C-reactive protein, lipoprotein A and other circulating macromolecules have been associated as independent risk factors for the development of vascular disease. As described above, these moieties appear to have the ability to act both as acute phase reactants as well as chronic procoagulant modifiers. In addition, these molecules have been documented to precipitate and/or exacerbate the majority of endothelial injury response, vascular smooth muscle cell proliferation and modify extracellular matrix processes and integrated mechanisms associated with acute vascular events as well as participate in xe2x80x9coxidative stressxe2x80x9d and xe2x80x9ccarbonyl stressxe2x80x9d that up-regulate vascular injury on the molecular level. The MDF system of the present invention is able to suppress this overreaction by depleting the wide range of molecular substrate reactants consumed by the biochemical maelstrom that occurs acutely in such disease states and to maintain such therapeutic reductions for an extended period of time.
In the context of secondary prevention and/or acute vascular event management, truly effective interventional technologies must be able to rapidly and substantially eliminate the broad spectrum of molecular pathogenic factors that have been implicated in the injury response cascades described above. Whether such interventions are pharmacological (xe2x80x98statinsxe2x80x99) or physiologic (apheresis), they must at once preserve those components necessary for cellular repair and healing (i.e. cytokines, signaling integrins and other, typically low molecular weight proteins), while at the same time they must substantially deplete the compounds responsible for injury (xe2x80x9cvascular injury risk factorsxe2x80x9d). This mandate represents the fundamental challenge of vascular disease management at present, especially given the time-to-effective-treatment requirements.
The present invention, preferably utilizing one of the RheoFilter(trademark) MDF systems, rapidly and efficiently depletes those circulating macromolecules larger than 250 xc3x85 or about 500 kDa in weight and heavier. These include; most isoforms of LDL-C, LDL-ox, fibrinogen, IgM, alpha-2 macroglobulin, lipoprotein A, apolipoprotein B, von Willebrand factor, vitronectin and many others identified as potential risk factors in vascular diseases. Recent studies have demonstrated that depletion of any one of these plasma components may improve endothelial cell function, increase blood flow, improve clinical outcomes or promote significant decreases in the morbidity and mortality associated with the management of acute coronary and other vascular events and their sequelae.
Other forms of apheresis for vascular intervention: In the quest for improved outcomes beyond drug therapy alone, four LDL apheresis technologies (dextran sulfate adsorption (Kaneka, Liposorber, Japan), antibody immunoadsorption (Baxter, Therasorb, Germany), Lp(a) immunoadsorption (Lipopak, Pocard, Russia) and heparin precipitation (HELP(copyright) System, Braun, Germany)) have recently been introduced for the treatment of familial hyperlipidemias (elevated LDL cholesterol). As expected, each of these technologies demonstrates a modest incremental ability to reverse arterial plaque formation, improve blood flow and increase exercise tolerance in some patients. However, the high costs and technical complexities associated with these methods have precluded them thus far as widely accepted options in those markets currently addressed by pharmaceutical and dietary interventions.
However, the principle reason for the lack of general acceptance is that the technologies are considerably too specific (removing LDL almost exclusively) to be of substantial benefit in moderating the majority of the mechanisms associated with acute vascular injury response/reperfusion damage. The HELP(copyright) system is only slightly better than the others in that it additionally depletes fibrinogen and some lipoprotein A (Lp(a)). The Lipopak system is far better at removing Lp(a) than any of the others, but each fails to deplete alpha-2 macroglobulin, IgM, IgA multimers, fibronectin, von Willebrand Factor, C-reactive protein, and many other of the macromolecules documented to be integral in the vascular damage cascades. This is in stark contrast to the actions of the RheoFilter(copyright) MDF systems.
A. In-Patient Medical Center Setting
Generally, the setting for therapeutic apheresis methods has been reserved for the hospital environment treating gravely ill patients with acute life-threatening diseases or recurrent exacerbations of such diseases. This has primarily been due to the severity of the patients being treated and subsequently the reimbursement available for treatment. However, the current overhead expense of the hospital environment adds significant costs to these procedures that need not necessarily be applied to apheresis treatments for relatively clinically stable yet chronically ill patients.
Historically, physicians are not trained in providing apheresis treatments outside of the hospital environment and remain unaware that apheresis methods can be applied to treat chronic, age-related, degenerative, inflammatory diseases; with AMD serving as the prototypical example in any setting outside of the hospital. Similarly, most patients with such diseases are not aware that they have a condition potentially treatable with the apheresis methods described herein or that such a potentially beneficial apheresis treatment option exists in such out-patient settings.
B. Out-patient xe2x80x9cOfficexe2x80x9d Setting
1. Rigdon Lentz UltraPheresis(trademark) center
Outpatient plasmapheresis therapy has been employed for removing low molecular weight proteins for the treatment of certain forms of solid tumors (Lentz, (1 999) Ther. Apher. 3, 40-49). This outpatient clinic practices a selective form of plasmapheresis known as UltraPheresis(trademark). This form of apheresis is more complicated and more expensive than Rheopheresis(copyright) blood filtration as described herein. Specifically, it removes TNF-alpha receptors, a particular low molecular weight fraction (55-75 kDa) from a cancer patient""s plasma as opposed to a high molecular weight fraction (i.e., greater than 500 kDa).
2. LDL apheresis treatment
One possible exception to the exclusive use of hospital or in-patient treatment settings involves the recent introduction of the use of LDL apheresis as a treatment for patients with clinically evident, refractory, drug resistant, Type II Familial Hypercholesterolemia - a chronic, slowly progressive, ultimately fatal illness. Currently, for reimbursement purposes, LDL patients obtain their treatment in hospital settings located away from their medical provider. These settings remain unmodified for the specific needs of these patients. In Europe, out-patient LDL apheresis clinics are used specifically for lipid lowering in select hyperlipidemic patients, however, these facilities are not designed to moderate rheologic diseases, nor are they disease specific clinics. Neither are the treatments provided systematized to be deliverable within an average physician""s office where the xe2x80x9cpoint of salexe2x80x9d use can be made to conveniently provide the most patients with the broadest available apheresis treatment options, at the lowest possible costs.
The present invention generally relates to therapeutic methods that involve the depletion of at least two species of Theologically active macromolecules from a patient""s plasma. Preferably, such macromolecules are depleted for a period of time and to a level that is effective to produce an improvement in a measurable endpoint or clinical improvement in a disease associated with relatively elevated levels of rheologically active macromolecules. The invention also relates to methods involving either the direct or indirect depletion of other plasma constituents of the high molecular weight fraction of plasma, and/or those constituents responsible for or supportive of those atherogenic, thrombotic and/or inflammatory cascades as described herein.
More specifically, the invention relates to methods in which the depleted rheologically active macromolecules (or high molecular weight fraction of plasma constituents) include cholesterol isoforms (VLDL, LDL and IDL), triglycerides, fibrinogen, alpha-2 macroglobulin tetramers, IgM, Lipoprotein A, fibronectin, vitronectin, and IgA. Preferably the depleted plasma constituents (or high molecular weight fraction) have a molecular weight greater than about 500,000 Daltons, or, such constituents (or macromolecules in such fraction) have an average size for a biologically active isoform that is greater than about 200 xc3x85 across the shortest diameter.
In a preferred embodiment, the depleted components are depleted to a level of at least about 50% of their levels in the patient compared to that prior to treatment. In an alternative preferred embodiment, the volume of plasma processed in a single treatment session ranges between about 80% and 120% of the patient""s total plasma volume. It is contemplated that such depletion may be accomplished by Rheopheresis(copyright) blood filtration, preferably using one of the series of RheoFilter(copyright) hollow fiber membranes. Generally, the time interval between successive Rheopheresis(copyright) blood filtration treatments ranges from about one day to about ten days and the total plasma volume processed in any one week period is at least about 200% of a patient""s total plasma volume, and that the successive treatment interval prior to the next dual session preferably is about 16 daysxc2x1 about 3 days.
It is contemplated that such therapeutic methods will be effective to produce in the patient one or more responses, such as: (1) increased microperfusion or capillary function; (2) improved immune response; or (3) extraction of tissue-bound RAM and to deplete the extracted RAM from the patient""s plasma. Such methods generally will be effective to produce in the patient a clinically observable improvement in a disorder characterized by elevated plasma levels of rheologically active macromolecules. Such disorders include: (1) age-related macular degeneration; (2) atherosclerosis; (3) rheumatoid arthritis; (4) autoimmune diseases; (5) Diabetes; (6) Alzheimer""s disease; (7) Procoagulant states, and (8) neurodegenerative diseases.
In another embodiment of the invention, Rheopheresis(copyright) blood filtration filters are provided in a form in which they are packaged together with a label or package insert (or the like) indicating its use for treatment of an age-related, degenerative or inflammatory disorder characterized by elevated plasma levels of Theologically active macromolecules, or any of the foregoing disorders.
The present invention also encompasses diagnostic methods that involve the measurement of the absolute or relative amounts of at least two rheologically active macromolecules depleted from a patient""s plasma by Rheopheresis(copyright) blood filtration. In particular, such methods involve making an assessment of plasma levels or rate of decrease of such levels post treatment, then making an assessment of the concomitant increase of the plasma levels of the depleted Theologically active macromolecules as they re-equilibrate toward pre-treatment levels. Patients are typically considered to have elevated levels if they are in the upper tertile or even more preferably in the upper quartile of ranges measured for human patients. In these settings, patients with elevations of certain of these macromolecules are generally considered to be xe2x80x9cat riskxe2x80x9d or exhibiting a xe2x80x9cprocoagulant statexe2x80x9d.
In a related aspect, the invention relates to methods of providing Rheopheresis(copyright) blood filtration treatment. The steps of such methods preferably include: (a) evaluating a candidate patient to identify whether the patient has a RAM associated disease and to determine that state and extent of that disease; (b) determining whether the patient exhibits elevated plasma levels of at least two RAMs; (c) declining to treat patients with Rheopheresis(copyright) blood filtration who are not likely to respond to treatment or who might be harmed by the treatment; (d) selecting a particular Rheopheresis(copyright) blood filtration treatment protocol appropriate for chronic versus acute medical situations; and (e) providing Rheopheresis(copyright) blood filtration treatment. Optionally, the step of selecting a particular Rheopheresis(copyright) blood filtration treatment protocol includes an evaluation of a data base containing data on other patients treated by Rheopheresis(copyright) blood filtration. Preferably, an additional step is the providing of disease-specific medical follow-up evaluations. The step of submitting data on the patient to a data base containing data on other patients treated by Rheopheresis(copyright) blood filtration also is contemplated.
In another aspect, the invention relates to an integrated apheresis treatment process including the steps of: (a) providing at least one dedicated out-patient, non-hospital, apheresis treatment facility; (b) locating and selecting ambulatory, community-dwelling patients potentially capable of benefiting from apheresis treatments within a community that can be served by said apheresis facility; (c) identifying and selecting from among said patients, by means which include measurement of serum levels of circulating rheologically active macromolecules in said patients, a subset of patients capable of benefiting from apheresis treatments; (d) performing apheresis treatments in sessions on the selected patients in said dedicated out-patient apheresis treatment facility; and (e) determining clinical endpoints to said apheresis treatments based upon reductions in serum levels of said theologically active macromolecules and correlations of clinical symptomatology through disease-specific testing and serial endpoint and clinical assessments.
In yet a further embodiment, the present invention relates to an apheresis treatment method, that includes the steps of: (a) identifying chronically ill patients having age-related, degenerative or inflammatory diseases, the chronically ill patients being considered candidates for an apheresis procedure; (b) storing patient profile data for the patient; (c) analyzing qualifying data for the chronically ill patient to determine applicability of an apheresis treatment; and (d) performing apheresis treatments in sessions on the chronically ill patient. Optionally, the storing step includes the storing at least one of medical history data, physical characteristic data, medical condition data, diagnosis data, historical procedure data, and clinical effect data. Also, optionally, the step of analyzing specifically includes one or more of these data elements: medical history, disease specific history, physical examination and interview data. Such analysis steps may also include comparing patient profile data with a composite patient profile that is generated using data from similar patients who have completed an analysis steps may also include comparing patient profile data with a composite patient profile that is generated using data from similar patients who have completed an apheresis treatment process, or the determining of at least one or more of the probability of apheresis treatment success, a potential degree of anticipated clinical outcomes based upon statistical normograms from an analysis of historical composite patient profiles, and a most appropriate initial apheresis treatment protocol.
Another embodiment of the invention provides an apheresis treatment qualification method, including the steps of: (a) identifying a chronically ill patient having an age-related, degenerative, atherogenic, thrombotic or inflammatory disease, said chronically ill patient being considered a candidate for an apheresis procedure; (b) storing patient profile data for said identified chronically ill patient; (c) receiving, from a centralized database system, a composite patient profile derived from other patients similarly situated to said identified chronically ill patient; (d) comparing said patient profile data with said received composite patient profile; and (e) determining based upon the comparison in step (d), whether said identified chronically ill patient would likely benefit from apheresis treatments. Optionally the storing step includes the storing of one or more of the patient""s medical history data, physical characteristic data, medical condition data, diagnosis data, historical procedure data, and clinical effect data.
The present invention also provides a method of screening patients for a Rheopheresis(copyright) blood filtration treatment. Such method includes: (a) identifying whether the patient has a RAM associated disease and determining that state and extent of that disease; (b) determining whether the patient exhibits elevated plasma levels of at least two RAMs; (c) selecting patients who are likely to respond to Rheopheresis(copyright) blood filtration treatment or who will not be harmed by the treatment; and, optionally, (d) selecting a particular Rheopheresis(copyright) blood filtration treatment appropriate for treating a specific RAM associated disease. The method may include the screening of a data base containing patient data from individuals treated by Rheopheresis(copyright) blood filtration to determine the most appropriate treatment protocol. In connection with that method, may be an additional step of submitting data in a patient profile to a data base containing patient data from other Rheopheresis(copyright) blood filtration treatment patients.
Yet another related aspect of the present invention is a treatment protocol generator for use in a system that endeavors to generate disease specific treatment protocols based on a patient profile. Preferably this treatment protocol generator comprises: (a) a treatment protocol derivation means for analyzing disease specific historical composite patient profiles to derive treatment protocols having enhanced therapeutic effect(s); (b) an identifying means for identifying particular data of a patient profile which will serve to optimize the disease specific apheresis treatment; and (c) a treatment protocol generating means for generating treatment protocol that, when executed, will enable optimization of the therapeutic effect of apheresis treatment. Such treatment protocol generators also may include: (a) a comparing means for comparing said data of said patient profile against a prescribed set of data to identify any of the treatment protocols substantially conforming to desired therapeutic result; and (b) classifying means for classifying the identified suitable treatment protocols in order of suitability based on the patient profile.
The identifying means of such a treatment protocol generator may include means for identifying, in accordance with said composite historical patient profiles, data from the database that will result a treatment protocol predicted to have a superior therapeutic effect. Preferably the data includes at least one of medical history data, physical characteristic data, medical condition data, diagnosis data, historical procedure data, clinical effect data, disease specific history data, physical examination data, and interview data. Also, preferably, the treatment protocol generator further includes an optimal set selecting means for selecting an optimal set of treatment parameters based on at least one of the following factors: (i) their respective predicted abilities to exhibit therapeutic results more closely matching the prescribed set of therapeutic results as indicated by said composite historical patient profiles; (ii) their respective predicted abilities to validate said composite historical patient profiles; (iii) their respective predicted abilities to discriminate between said composite historical patient profiles; (iv) their respective predicted abilities to induce superior therapeutic response; and (v) similarity between their disease specific characteristics and those in composite historical patient profile database whose therapeutic response most closely conform to the desired therapeutic response. The protocol generator also may include a means for selecting the optimal set by individually ranking the treatment parameters based on at least one of factors (i)-(v) or combinations thereof.
The present invention also provides an apheresis treatment data collection and treatment system, comprising: (a) a plurality of interconnected computer systems located at a respective plurality of apheresis treatment sites, said plurality of interconnected computer systems being configured to receive input reflective of apheresis treatment parameters and clinical effects produced by apheresis treatments, wherein at least one of said plurality of interconnected computer systems is located at a dedicated out-patient apheresis treatment facility; and (b) a centralized database system including a storage facility that stores apheresis treatment parameter data and clinical effects data that are received from said plurality of interconnected computer systems, said centralized database system further including a means for creating a composite patient profile based upon apheresis treatment data that is collected for patients treated at said plurality of apheresis treatment sites. Optionally, the plurality of interconnected computer systems and the centralized database system are interconnected to form a computer network and may also be connected to the Internet.
A related aspect of the invention provides methods for storing and processing input reflective of apheresis treatment parameters and clinical effects produced by apheresis treatments in a apheresis treatment data collection and treatment system, said method comprising the steps of: (a) configuring a plurality of interconnected computer systems located at a respective plurality of apheresis treatment sites to receive input reflective of apheresis treatment parameters and clinical effects produced by apheresis treatments, wherein at least one of said plurality of interconnected computer systems is located at a dedicated out-patient apheresis treatment facility; and (b) storing apheresis treatment parameter data and clinical effects data that are received from said plurality of interconnected computer systems in a centralized database system, said centralized database system further including a means for creating a composite patient profile based upon apheresis treatment data that is collected for patients treated at said plurality of apheresis treatment sites.
A further and related aspect of the invention involves an apheresis treatment data collection and treatment system. Such a system includes: (a) first means for enabling a user to enter information about a patient in a computer database; (b) second means for creating a summary of the information entered into the local computer database; (c) third means for periodically transmitting the summarized information to a data management system database; (d) fourth means for allowing local users to search the data management system database for a specific patient profile; (e) fifth means for performing data aggregation and analysis on the data management system database and for producing reports based on a search criterion; and (f) sixth means for allowing the local users to download the produced reports. Preferably, the sixth means for allowing enables licensed users to establish the efficacy of RheoThera(copyright), Rheopheresis, VasoTherapy, AngioTherapy and like apheresis means.